Department of General Thoracic Surgery and Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Int J Cancer. 2021 Jun 15;148(12):3008-3018. doi: 10.1002/ijc.33499. Epub 2021 Feb 19.
Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.
特发性肺纤维化（IPF）患者发生肺癌（包括鳞状细胞肺癌，SCC）的风险较高，而 SCC 通常预后较差。虽然 IPF 后癌症发生的分子基础尚未完全阐明，但我们最近报道了 SCC 中频繁和不频繁的 DNA 高甲基化的两种表观遗传表型，以及不频繁高甲基化表型与 IPF 相关 SCC 的关联。在这里，我们使用人类肺癌panel 对有和无 IPF 的 SCC 进行了靶向外显子测序，以研究与 IPF 相关 SCC 的遗传基础。有和无 IPF 的 SCC 显示出相似数量的总突变（137±22 与 131±27，P=0.5）、非同义突变（72±14 与 69±16，P=0.5）、插入缺失（3.0±3.5 与 3.0±3.9，P=1）和同义突变（62±9.1 与 60±12，P=0.5）。SCC 中最主要的特征是特征 1。SETD2 和 NFE2L2 突变与 IPF 显著相关（44%与 13%，P=0.03 对于 SETD2；38%与 10%，P=0.04 对于 NFE2L2）。通过拷贝数变异分析评估的 MYC 扩增也与 IPF 显著相关（18.8%与 0%，P=0.04）。在频繁高甲基化的 SCC 中观察到 TP53 和 CDKN2A 突变相对频繁（P=0.02 对于 TP53 和 P=0.06 对于 CDKN2A）。生存分析表明 SETD2 突变与预后较差显著相关（P=0.04）。总的来说，我们发现 SETD2 和 NFE2L2 突变和 MYC 扩增在 IPF 相关 SCC 中频繁发生，并且 SETD2 突变与预后较差相关。
